Maintaining Hydrophobic Drug Supersaturation in a Micelle Corona Reservoir

Ziang Li, Theodore I. Lenk, Letitia J. Yao, Frank S. Bates, Timothy P. Lodge

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

Two poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide) (PND) statistical copolymers and a series of three poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide)-b-polystyrene (PND-b-PS-C 12) diblock polymers were synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization, in which the molecular weight of the thermoresponsive PND corona block was held constant while the polystyrene core block length was varied. The corona thickness and density of the micelles in phosphate-buffered saline (PBS, pH = 6.5) were quantified by a combination of dynamic light scattering (DLS) and small-angle X-ray scattering (SAXS). Two hydrophobic model drugs, phenytoin and nilutamide, were used to examine the drug-polymer interactions in aqueous solution. Intermolecular interactions between the diblock polymer micelle corona and both drugs were revealed by 2D 1H nuclear Overhauser effect spectroscopy (NOESY). The drug-polymer "binding" strength, quantified by diffusion ordered NMR spectroscopy (DOSY), increased as corona density of the diblock polymer micelle increased for both drugs. The in vitro dissolution of the amorphous solid dispersions was systematically investigated as a function of drug type, drug loading, and the solution-state assembly of the polymers by using either a selective or nonselective spray drying solvent. Forming micelles prior to spray drying significantly enhanced phenytoin dissolution and supersaturation maintenance for the diblock polymers by storing the drug molecules in the corona.

Original languageEnglish (US)
Pages (from-to)540-551
JournalMacromolecules
Volume51
Issue number2
DOIs
StatePublished - Jan 23 2018

Bibliographical note

Funding Information:
This study was funded by The Dow Chemical Company through Agreement 224249AT with the University of Minnesota. The authors gratefully thank Professor Theresa M. Reineke, Professor Marc A. Hillmyer, Dr. Jodi Mecca, Dr. Jin Zhao, Dr. Robert L. Schmitt, Dr. William Porter, Dr. Jeffrey M. Ting, Peter W. Schmidt, Lindsay M. Johnson, Anatolii A. Purchel, and Dr. Ralm G. Ricarte for helpful discussions. Parts of this work were performed at the DuPont−Northwestern− Dow Collaborative Access Team (DND-CAT) located at Sector 5 of the Advanced Photon Source (APS). DND-CAT is supported by E.I. DuPont de Nemours & Co., The Dow Chemical Company, and Northwestern University. Use of the APS, an Office of Science User Facility operated for the U.S. Department of Energy (DOE) Office of Science by Argonne National Laboratory, was supported by the U.S. DOE under Contract DE-AC02-06CH11357. This work benefited from the use of the SasView application, originally developed under NSF Award DMR-0520547. SasView contains code developed with funding from the European Union’s Horizon 2020 research and innovation programme under the SINE2020 project, Grant Agreement No. 654000. Parts of this work were carried out in the College of Science & Engineering Characterization Facility, University of Minnesota, which has received capital equipment funding from the NSF through the UMN MRSEC program under Award DMR-1420013. NMR instrumentation was supported by the Office of the Vice President of Research, College of Science and Engineering, and the Department of Chemistry at the University of Minnesota; the Bruker HD NMR was supported by the Office of the Director, National Institutes of Health under Award S10OD011952. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Publisher Copyright:
© 2018 American Chemical Society.

How much support was provided by MRSEC?

  • Shared

Reporting period for MRSEC

  • Period 4

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